Parkinson's disease is a common neurodegenerative disease accompanied by significant functional disability, resulting from neurodegeneration in the substantia nigra and other brain regions. LRRK2 mutations constitute the most common identified cause of human PD, accounting for up to 20% of PD in some populations. The most common mutation, G2019S, is present in up to one percent of apparently sporadic PD in European and North American populations, and causes typical late onset PD, with response to L-DOPA, and Lewy body pathology. We have previously reported that expression of mutant LRRK2 causes substantial cell toxicity in cell culture, and we have recently found that toxicity is mediated via kinase activity of mutant LRRK2. We now propose to study mouse models expressing either full-length human LRRK2 with the G2019S mutation or wild-type. We have generated transgenic mice expressing LRRK2 under the control of the prion promoter, which have a moderate phenotype, and we have more recently generated homozygous mice with higher expression levels and normal development. In Specific Aim 1 we will characterize survival and behavior of the homozygous transgenic mice expressing mutant G2019S LRRK2, and perform an initial assessment of neuronal loss and Lewy bodies, or other PD-like neuropathology in appropriate cellular populations. In Specific Aim 2 we will cross the heterozygous mice with mice expressing a truncated fragment of alpha-synuclein using the TH promoter. A new model of PD which reproduces aspects of phenotypes seen in the human disease would be of great benefit. Future studies of the role of kinase activity could clarify pathogenesis. Furthermore LRRK2 kinase may be an excellent therapeutic target, and mouse models would be valuable for preclinical therapeutic trials. PUBLIC HEALTH RELEVANCE: We propose to generate new mouse models of Parkinson's disease. LRRK2 mutations constitute the most common identified cause of human PD, accounting for up to 20% of PD in some populations. We have previously reported that expression of mutant LRRK2 causes substantial cell toxicity in cell culture, and we have recently found that toxicity is mediated via kinase activity of mutant LRRK2. A new mouse model of PD which reproduces aspects of phenotypes seen in the human disease would be of great benefit. Future studies of the role of kinase activity could clarify pathogenesis. Furthermore LRRK2 kinase may be an excellent therapeutic target, and mouse models would be valuable for preclinical therapeutic trials.